The aim of this investigation is to examine cholesterol and cholestanol metabolism in patients with cerebrotendinous xanthomatosis (CTX), atherosclerosis and gallstones. Specifically, we shall continue to define the biochemical defect in the rare inherited lipid storage disease, CTX. Current evidence indicates that the defect is a block in the side chain oxidation of cholesterol to a carboxylic acid as part of the cholic acid synthetic pathway with the accumulation of 5 beta-cholestanol-3 alpha, 7 alpha, 12 alpha, 25-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 xi, 25-pentol. We shall investigate the role of these two bile alcohols as precursors of cholic acid in normal man and determine the specific enzymatic defect in CTX liver that results in the accumulation of these bile alcohols. The importance of this work is the potential discovery of a new pathway of cholic acid synthesis involving C25-hydroxy bile alcohol since current opinions indicate that cholic acid is formed only by C26-hydroxy compounds. We plan to measure the activities of the two hepatic rate-determining enzymes for cholesterol and bile acid synthesis, HMG CoA reductase and cholesterol 7 alpha-hydroxylase respectively, in patients with gallstones and hyperlipidemia. The purpose is to relate relative rates of cholesterol synthesis and degradation with plasma cholesterol levels and the concentration of cholesterol in the bile. This information will tell us not only about the mechanism of the cholesterol overload but will enable us to formulate more effective therapy, i.e., a cholesterol inhibitor for overactive cholesterol synthesis or an agent that fluxes cholesterol when the problem is limited removal. BIBLIOGRAPHIC REFERENCES: Shefer, S., F.W. Cheng, B. Dayal, S. Hauser, G.S. Tint, G. Salen and E.H. Mosbach: A 25-hydroxylation pathway of cholic acid biosynthesis in man and rat. J. Clin. Invest. 57:897-903, 1976. Nicolau, G., B.I. Cohen, G. Salen, E.H. Mosbach: Studies on the 12 alpha and 26-hydroxylation of bile alcohols by rabbit liver microsomes. Lipids 11:148-152, 1976.